Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the western male population. When this carcinoma has locally or distantly spread, no curative therapy can be offered. Therefore, efforts to control the disease (i.e., to decrease prostate cancer mortality) have focused on increasing detection of the cancer while it is still locally confined and potentially curable. Studies aimed at the early detection of prostate cancer have demonstrated an appreciable increase in the detection of organ-confined potentially curable prostate cancers. However, it has not yet been demonstrated that the increased detection rate will decrease the prostate cancer-specific mortality rates. On the other hand, there is also no evidence that early diagnosis will decrease the mortality rates. Both in the United States and in Europe, discussions on the efficacy and acceptability of screening programs, the issue of overdiagnosis and overtreatment and the chances that early treatment will lead to reduced prostate cancer morbidity and mortality, are still ongoing and make early detection of prostate cancer a controversial issue (Schröder, Urology 46: 6270 (1995)).
Measurements of serum concentrations of prostatic marker enzymes have recognized value in the clinical detection, diagnosis and management of prostate cancer. The two most widely used prostatic marker enzymes are prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). Normally, both enzymes are secreted from the prostatic epithelial cells into the seminal fluid, but in patients with prostatic disease they leak into the circulation, where they can be detected by means of immunological assays (Armbruster, Clin. Che. 39: 181–95 (1993)).
Prostatic acid phosphatase, one of the earliest serum markers for prostate, has an as yet undetermined function and is one of the most predominant protein components in human prostatic secretions. The use of PAP as a marker for prostatic tumors is complicated by the reported structural similarities between the prostate-specific acid phosphatase and the lysosomal acid phosphatase occurring in all tissues. Furthermore, there is a tendency towards lower PAP mRNA and protein levels in prostate cancer in comparison with benign prostatic hyperplasia (BPH). In recent years, PAP measurements were superseded by serum PSA measurements in the clinical management of prostate cancer.
Prostate-specific antigen was identified by several groups in the 1970's as a prostate-specific protein from the seminal fluid. In 1979, it was purified as an antigen from prostate cancer tissue. Further research showed that PSA is produced exclusively by the columnar epithelial cells of the prostate and periuretural glands. Normal prostate epithelium and benign hyperplastic tissue actually produce more PSA mRNA and protein than does prostate cancer tissue. Furthermore, it was shown that loss of differentiation of prostatic carcinomas is associated with a decrease in the level of intraprostatic PSA.
Abnormalities in prostate architecture occurring as a result of prostatic disease lead to an increased leakage of PSA (and PAP) into the serum and make serum PSA measurements a marker for prostate cancer. Despite the fact that early studies have indicated that diagnostic PSA testing would be hampered by the fact that it lacked specificity in differentiating between BPH and prostate cancer, PSA testing was introduced in 1986 and revolutionized the management of patients with prostate cancer. Increased knowledge on the organ specificity of PSA and the relationship of elevated serum PSA levels to prostate disease as well as improvement of biopsy techniques and histological evaluation, led to a appreciation of the clinical value of PSA testing, a utility not yet achieved by any other (prostate) tumor marker. Cloning of the gene that encodes PSA revealed that it is a member of the human kallikrein gene family and resulted in the development of new approaches to the use of PSA as a marker: the very sensitive reverse transcriptaske polymerase chain reaction (RT-PCR) method is used to detect extremely small numbers of malignant prostate cells in blood samples from prostate cancer patients and might provide a sensitive tool to identify patients with micrometastatic disease (Moreno et al., Cancer Res. 52: 6110–12 (1992); and Katz et al., Urology 43: 765–75 (1994)).
Prostate-specific membrane antigen (PSM) was originally identified using an antibody developed by immunizing mice with the membrane fraction of LNCaP human prostatic adenocarcinoma cells. Like PAP and PSA, PSM can be detected in normal prostate, BPH and prostate cancer and is absent from most other tissues. Also for PSM, RT-PCR studies have been developed to detect circulating prostate cancer cells, however, further investigations are required to establish the usefulness of PSM as marker for prostatic cancer.
In summary, PSA is currently recognized as the premier marker for prostatic cancer, being useful for screening selected populations of patients with symptoms indicative of prostate cancer and for monitoring patients after therapy, especially after surgical prostatectomy (measurable levels of PSA indicate residual disease or metastasis and increasing PSA concentrations indicate recurrent disease). The significant weaknesses of PSA as a tumor marker are that (1) PSA is not able to always distinguish prostate cancer from BPH; and (2) that its expression decreases with loss of differentiation of carcinomas.
In view of the fact that advanced prostate cancer remains a life threatening disease reaching a very significant proportion of the male population, there remains a need for the development of new treatment and diagnostic modalities for (late stage) prostate cancer.
The present invention seeks to meet these and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference.